US8785663B2 - Polymorphic forms of Lubiprostone - Google Patents

Polymorphic forms of Lubiprostone Download PDF

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Publication number
US8785663B2
US8785663B2 US13/575,680 US201113575680A US8785663B2 US 8785663 B2 US8785663 B2 US 8785663B2 US 201113575680 A US201113575680 A US 201113575680A US 8785663 B2 US8785663 B2 US 8785663B2
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Prior art keywords
lubiprostone
crystalline form
approximately
peak
apo
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Expired - Fee Related
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US13/575,680
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US20130096325A1 (en
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Alfredo Paul Ceccarelli
Kiran Kumar Kothakonda
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Apotex Pharmachem Inc
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Apotex Pharmachem Inc
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Assigned to APOTEX PHARMACHEM INC. reassignment APOTEX PHARMACHEM INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CECCARELLI, ALFREDO PAUL, KOTHAKONDA, KIRAN KUMAR
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to polymorphic forms of Lubiprostone.
  • Lubiprostone (1) is an E1 type prostaglandin derivative. It is marketed in USA as Amitiza® and is used for the treatment of idiopathic chronic constipation, irritable bowel syndrome and post operative ilues. The use of Lubiprostone softens the stool, increases motility, and promotes spontaneous bowel movements (SBM). Chemically, Lubiprostone is 7-[(2R,4aR,5R,7aR)-2-(1,1-difluoropentyl)-2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl]heptanoic acid ( Drugs of the Future, 2004, 29(4); 336-341):
  • U.S. Pat. No. 5,117,042 discloses a method of treatment for improving encephalic function which comprises administering to a subject in need of such treatment a 15-keto-prostaglandin compound in an amount effective for improvement of encephalic function.
  • U.S. Pat. No. 5,284,858 discloses 13,14-dihydro-15-keto prostaglandins E having remarkable preventive effects against ulcers. Further, according to U.S. Pat. No. 5,284,858, 13,14-dihydro-15-ketoprostaglandins E have an advantage that they have none of the side effects which prostaglandin E intrinsically has, or can remarkably reduce such effects of the prostaglandin E. According to U.S. Pat. No. 5,284,858, 13,14-dihydro-15-keto prostaglandins E are effective for animal and human use for treatment and prevention of ulcers, such as duodenal ulcer and gastric ulcer.
  • U.S. Pat. No. 6,414,016 provides an anti-constipation composition containing a halogenated-bi-cyclic compound as an active ingredient in a ratio of bi-cyclic/mono-cyclic structure of at least 1:1.
  • the halogenated-bi-cyclic compound in U.S. Pat. No. 6,414,016 is represented by Formula (I):
  • X1 and X2 are preferably both fluorine atoms.
  • the composition can be used to treat constipation without substantive side-effects, such as stomachache.
  • WO2009/121228 discloses a Lubiprostone crystal, its preparation process, its pharmaceutical composition or kit, and its use for the preparation of a pharmaceutical composition for treating gastroenteropathy, especially constipation.
  • the characteristic peaks of 2 ⁇ reflection angle in X-ray powder diffraction spectra of the crystal include 14.6 ⁇ 0.2°, 17.0 ⁇ 0.2° and 19.6 ⁇ 0.2°.
  • the crystal has the advantages of high purity, stable property, and convenient storage and usage compared with amorphous Lubiprostone.
  • the present invention relates, at least in part, to a crystalline form of Lubiprostone, namely a polymorphic form of Lubiprostone termed herein as APO-II and to processes for preparing APO-II.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 8.98.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 13.53 together with any one or more peaks described herein.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 18.06 together with any one or more peaks described herein
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.57 together with any one or more peaks described herein
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 20.80 together with any one or more peaks described herein
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern comprising a peak, in terms of 2-theta, at approximately 22.74 together with any one or more peaks described herein
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a 1% KBr FTIR spectrum comprising peaks, in terms of cm ⁇ 1 , at approximately 3470, 2938, 1738, 1710, 1473, 1383, 1313, 1210, 1159, 979, 891, 793, 726 and 580.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a FTIR spectrum substantially as shown in FIG. 2 .
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram comprising an endothermic peak with a peak onset temperature of approximately 76° C. and a peak maximum of approximately 77° C.
  • Illustrative embodiments of the present invention provide a crystalline form of Lubiprostone having a DSC thermogram substantially as shown in FIG. 3 .
  • Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: distilling a Lubiprostone filtrate to near dryness thereby forming a residue; dissolving the residue in a first organic solvent thereby forming a residue solution; adding a second organic solvent to the residue solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
  • Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding a fourth organic solvent to the Lubiprostone solution thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
  • Illustrative embodiments of the present invention provide a process to prepare APO-II comprising: dissolving Lubiprostone in a third organic solvent thereby forming a Lubiprostone solution; adding the Lubiprostone solution to a fourth organic solvent thereby forming a mixture; stirring the mixture until precipitation occurs thereby forming a precipitate; filtering the precipitate thereby isolating APO-II.
  • Illustrative embodiments of the present invention provide a pharmaceutical formulation comprising APO-II.
  • FIG. 1 is a powder X-ray diffraction (PXRD) diffractogram of APO-II.
  • FIG. 2 is a Fourier transform infrared (FTIR) spectrum of APO-II.
  • FIG. 3 is a differential scanning calorimetry (DSC) thermogram of APO-II.
  • the term “substantially similar” means that the subject diffractogram, spectrum and/or data presented in a graph encompasses all diffractograms, spectra and/or data presented in graphs that vary within acceptable boundaries of experimentation that are known to a person of skill in the art. Such boundaries of experimentation will vary depending on the type of the subject diffractogram, spectrum and/or data presented in a graph, but will nevertheless be known to a person of skill in the art.
  • the term “approximately” means that the peak may vary by ⁇ 0.2 degrees 2 ⁇ of the subject value.
  • the term “approximately” means that the peak may vary by ⁇ 5 cm ⁇ 1 of the subject value.
  • the term “approximately” means that the peak may vary by ⁇ 1 degree of the subject value.
  • the term “peak” refers to a feature that one skilled in the art would recognize as not attributing to background noise.
  • an intensity of a peak obtained may vary quite dramatically. For example, it is possible to obtain a relative peak intensity of 0.01% when analyzing one sample of a substance, but another sample of the same substance may show a much different relative intensity for a peak at the same position. This may be due, in part, to the preferred orientation of the sample and its deviation from the ideal random sample orientation, sample preparation and the methodology applied. Such variations are known and understood by a person of skill in the art.
  • the present invention comprises a crystalline form of Lubiprostone which is a polymorphic form referred to herein as APO-II.
  • APO-II a polymorphic form
  • An illustrative PXRD diffractogram of APO-II is given in FIG. 1 .
  • An illustrative FTIR spectrum of APO-II is given in FIG. 2 .
  • An illustrative DSC thermogram of APO-II is given in FIG. 3 .
  • Illustrative relative peak intensities of APO-II are illustrated below in Table 1.
  • APO-II may be prepared according to Scheme 1.
  • Lubiprostone may be prepared, for instance, as illustrated in Scheme 1.
  • the Lubiprostone filtrate referred to in Scheme 1 may be a starting material for use in making APO-II.
  • the present invention provides a process of preparing APO-II comprising:
  • the first organic solvent used to dissolve the residue may be any organic solvent. Often the first organic solvent may be ethyl acetate, methyl tert-butyl ether (MTBE) and mixtures thereof.
  • the volume of the first organic solvent may be about 0.5 volumes to about 5 volumes.
  • the volume of the first organic solvent may be about 0.5 volumes to about 1.5 volumes.
  • the second organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the second organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof.
  • the volume of the second organic solvent may be about 1 volumes to about 15 volumes.
  • the volume of the second organic solvent may be about 3 volumes to about 10 volumes.
  • the precipitation of APO-II may be performed at a temperature of about 5° C. to about 40° C.
  • the temperature for precipitation may be about 15° C. to about 30° C. Often the temperature for precipitation is about 20° C. to about 25° C.
  • the present invention provides a process of preparing APO-II comprising:
  • the Lubiprostone dissolved in step h may be any Lubiprostone (e.g. any polymorphic form and/or mixtures thereof).
  • the third organic solvent used to dissolve the Lubiprostone may be any organic solvent. Often the third organic solvent may be ethyl acetate, MTBE and mixtures thereof. The volume of the third organic solvent may be about 0.5 volumes to about 5 volumes. The volume of the third organic solvent may be about 0.5 volumes to about 1.5 volumes.
  • the fourth organic solvent used may be any organic solvent which exhibits anti-solvent properties with Lubiprostone. Often the fourth organic solvent is petroleum ether, hexanes, heptanes or mixtures thereof.
  • the volume of the fourth organic solvent may be about 1 volumes to about 15 volumes.
  • the volume of the fourth organic solvent may be about 3 volumes to about 10 volumes.
  • the precipitation of APO-II may be performed at a temperature of about 5° C. to about 40° C.
  • the temperature for precipitation may be about 15° C. to about 30° C.
  • the reaction temperature may be about 20° C. to about 25° C.
  • the amount of APO-II used in step k may be about 0.01 to about 50 w/w percent relative to the amount of Lubiprostone added in step k.
  • polymorphic Form APO-II Lubiprostone may be produced.
  • Powder X-Ray Diffraction Analysis The data were acquired on a PANanalytical X-Pert Pro MPD diffractometer with fixed divergence slits and an X-Celerator RTMS detector.
  • the diffractometer was configured in Bragg-Brentano geometry; data was collected over a 2 theta range of 3 to 40 using CuK ⁇ radiation at a power of 40 mA and 45 kV. CuK ⁇ radiation was removed using a divergent beam nickel filter. A step size of 0.017 degrees was used. A step time of 50 seconds was used. Samples were rotated at 1 Hz to reduce preferred orientation effects. The samples were prepared by the back-loading technique.
  • FTIR Fourier Transform Infrared
  • DSC Differential Scanning calorimetry
  • the amine salt was isolated by filtration and dried to give Lubiprostone tert-butylamine salt (20 g).
  • the amine salt was suspended in ethyl acetate (6 volumes) and water (3 volumes).
  • the resulting bi-phasic mixture was adjusted to about pH 5 with formic acid.
  • the organic layer was separated and concentrated to obtain Lubiprostone as a syrup.
  • the syrup produced Lubiprostone (1, 12 g) in approximately 70% recovery.
  • the Lubiprostone filtrate was concentrated to near-dryness.
  • Example 2 The procedure outlined in Example 1 to obtain the concentrated Lubiprostone filtrate was followed. To the concentrated Lubiprostone filtrate (300 mg) was added ethyl acetate (1 volume). The mixture was stirred at room temperature until dissolution was achieved. To the mixture was added petroleum ether (3 volumes). The mixture was stirred at room temperature until precipitation occurred. A product was isolated by filtration, washed and dried under vacuum to give APO-II (230 mg).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US13/575,680 2010-01-28 2011-01-28 Polymorphic forms of Lubiprostone Expired - Fee Related US8785663B2 (en)

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US29917610P 2010-01-28 2010-01-28
US61299176 2010-01-28
US13/575,680 US8785663B2 (en) 2010-01-28 2011-01-28 Polymorphic forms of Lubiprostone
PCT/CA2011/000088 WO2011091513A1 (fr) 2010-01-28 2011-01-28 Formes polymorphiques de la lubiprostone

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109096320A (zh) * 2017-06-21 2018-12-28 黄冈鲁班药业股份有限公司 苯甲酰科里内酯的制备方法

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CN104140410B (zh) * 2013-05-09 2017-12-15 江苏豪森药业集团有限公司 鲁比前列酮的制备方法
CN104710398A (zh) * 2015-02-17 2015-06-17 齐鲁制药有限公司 鲁比前列酮的新晶型及其制备方法
CN107474033A (zh) * 2016-06-07 2017-12-15 北京深蓝海生物医药科技有限公司 一种精制鲁比前列酮的方法
US10253011B1 (en) * 2018-07-13 2019-04-09 Chirogate International Inc. Lubiprostone crystals and methods for preparing the same

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009121228A2 (fr) * 2008-04-01 2009-10-08 上海天伟生物制药有限公司 Cristal de lubiprostone, son procédé de préparation et son utilisation
WO2010083597A1 (fr) 2009-01-22 2010-07-29 Apotex Pharmachem Inc. Méthodes de fabrication de lubiprostone et de ses intermédiaires
US20110112312A1 (en) * 2008-08-29 2011-05-12 Alphora Research Inc. Prostaglandin synthesis and intermediates for use therein

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6414016B1 (en) 2000-09-05 2002-07-02 Sucampo, A.G. Anti-constipation composition

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009121228A2 (fr) * 2008-04-01 2009-10-08 上海天伟生物制药有限公司 Cristal de lubiprostone, son procédé de préparation et son utilisation
US20110028541A1 (en) * 2008-04-01 2011-02-03 Shanghai Techwell Biopharmaceutical Co., Ltd Lubiprostone crystal, the use and the method for the preparation thereof
US20110112312A1 (en) * 2008-08-29 2011-05-12 Alphora Research Inc. Prostaglandin synthesis and intermediates for use therein
WO2010083597A1 (fr) 2009-01-22 2010-07-29 Apotex Pharmachem Inc. Méthodes de fabrication de lubiprostone et de ses intermédiaires

Non-Patent Citations (1)

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Title
Viscomi, G.C., Crystal forms of rifaximin and their effect on pharmaceutical properties (2008) Cryst. Eng. Commun. 10: 1074-1081. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109096320A (zh) * 2017-06-21 2018-12-28 黄冈鲁班药业股份有限公司 苯甲酰科里内酯的制备方法
CN109096320B (zh) * 2017-06-21 2021-04-16 黄冈鲁班药业股份有限公司 苯甲酰科里内酯的制备方法

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EP2536705A4 (fr) 2013-08-07
US20130096325A1 (en) 2013-04-18
CA2788334A1 (fr) 2011-08-04
WO2011091513A1 (fr) 2011-08-04
EP2536705A1 (fr) 2012-12-26

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